14-23357617-T-C

Variant names:

• chr14-23357617-T-C
• rs1889970878
• NM_005864.4:c.1295A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005864.4(EFS):​c.1295A>G​(p.Asp432Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000708 in 1,411,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: EFS NM_005864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.43

Genes affected

EFS (HGNC:16898): (embryonal Fyn-associated substrate) The protein encoded by this gene is a member of the CAS (CRK-associated substrate) family of adaptor proteins which typically serve as scaffolds for the assembly of larger signaling complexes. These complexes form at the cell surface where integrin binding leads to the subsequent phosphorylation of a CAS protein. Additional binding of SRC family kinases leads to CAS hyperphosphorylation and the creation of binding sites for CRK and other proteins that cause actin cytoskeleton reorganization. This gene plays a role in integrin-mediated cell attachment, spreading, and migration and also plays a role in both normal and malignant cellular transformation. This broadly expressed gene has been shown to play a role in neurite outgrowth and its expression in the thymus and lymphocytes is important for T cell maturation and the development of immunological self-tolerance. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFS	NM_005864.4	c.1295A>G	p.Asp432Gly	missense_variant	Exon 6 of 6	ENST00000216733.8	NP_005855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFS	ENST00000216733.8	c.1295A>G	p.Asp432Gly	missense_variant	Exon 6 of 6	1	NM_005864.4	ENSP00000216733.3
EFS	ENST00000351354.3	c.1016A>G	p.Asp339Gly	missense_variant	Exon 5 of 5	1		ENSP00000340607.3
EFS	ENST00000429593.6	c.788A>G	p.Asp263Gly	missense_variant	Exon 6 of 6	2		ENSP00000416684.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1411632 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 694144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.26e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1295A>G (p.D432G) alteration is located in exon 6 (coding exon 6) of the EFS gene. This alteration results from a A to G substitution at nucleotide position 1295, causing the aspartic acid (D) at amino acid position 432 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.3	M;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0050	D;D;D
Sift4G	Pathogenic	0.0	D;T;D
Polyphen		1.0	D;.;D
Vest4		0.80
MutPred		0.61		Loss of sheet (P = 0.0457);.;.;
MVP		0.67
MPC		0.61
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.85
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1889970878; hg19: chr14-23826826;